Malaria circumsporozoite protein binds to heparan sulfate proteoglycans associated with the surface membrane of hepatocytes.

Frevert, Ute; Sinnis, Photini; Cerami, Anthony; Shreffler, Wayne G.; Takács, B.; Nussenzweig, Victor

doi:10.1084/jem.177.5.1287

Cited by 316 publications

(239 citation statements)

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“…Previous research found that some pathogens use a surface heparin-binding protein to bind the host cells (56)(57)(58)(59)(60)(61). However, no HBM was identified in SWP7 or SWP9.…”

Section: Discussionmentioning

confidence: 83%

Interaction and Assembly of Two Novel Proteins in the Spore Wall of the Microsporidian Species Nosema bombycis and Their Roles in Adherence to and Infection of Host Cells

et al. 2015

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Microsporidia are obligate intracellular parasites with rigid spore walls that protect against various environmental pressures. Despite an extensive description of the spore wall, little is known regarding the mechanism by which it is deposited or the role it plays in cell adhesion and infection. In this study, we report the identification and characterization of two novel spore wall proteins, SWP7 and SWP9, in the microsporidian species Nosema bombycis. SWP7 and SWP9 are mainly localized to the exospore and endospore of mature spores and the cytoplasm of sporonts, respectively. In addition, a portion of SWP9 is targeted to the spore wall of sporoblasts earlier than SWP7 is. Both SWP7 and SWP9 are specifically colocalized to the spore wall in mature spores. Furthermore, immunoprecipitation, far-Western blotting, unreduced SDS-PAGE, and yeast two-hybrid data demonstrated that SWP7 interacted with SWP9. The chitin binding assay showed that, within the total spore protein, SWP9 and SWP7 can bind to the deproteinated chitin spore coats (DCSCs) of N. bombycis. However, binding of the recombinant protein rSWP7-His to the DCSCs is dependent on the combination of rSWP9 -glutathione S-transferase (GST) with the DCSCs. Finally, rSWP9-GST, anti-SWP9, and anti-SWP7 antibodies decreased spore adhesion and infection of the host cell. In conclusion, SWP7 and SWP9 may have important structural capacities and play significant roles in modulating host cell adherence and infection in vitro. A possible major function of SWP9 is as a scaffolding protein that supports other proteins (such as SWP7) that form the integrated spore wall of N. bombycis.M icrosporidia, which infect numerous vertebrate and invertebrate species, are a specific group of obligate spore-forming, intracellular, and unicellular eukaryotic protists (1). The microsporidian species Nosema bombycis causes pebrine, a disease that was common in Europe, America, and Asia during the mid19th century and still causes heavy losses in silk-producing countries, such as China and India (1). It was first recognized in 1857 by Nägeli (2). Recently, phylogenetic analyses based on conserved proteins (3-5), ribosomal DNA (rDNA) sequences (6, 7), and complete sequencing of the Encephalitozoon cuniculi genome (8) have suggested that microsporidia, which undergo a highly reductive evolution, are closely related to fungi (9). However, the N. bombycis genome has greatly expanded due to transposable elements and gene duplications (10).The microsporidian spore wall, which is usually comprised of an electron-dense proteinaceous outer layer (exospore) of 25 to 30 nm and an electron-transparent chitinous inner layer (endospore) of 30 to 35 nm, maintains the spore's morphology and helps the mature spore resist the outer environment (11-13). Although chitin is the major component of the spore wall, only one chitin-associated protein has been identified. The chitin deacetylase activity of E. cuniculi (EcCDA) has been confirmed to be expressed during sporogonic stages (14). Currently, the deprot...

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“…Previous research found that some pathogens use a surface heparin-binding protein to bind the host cells (56)(57)(58)(59)(60)(61). However, no HBM was identified in SWP7 or SWP9.…”

Section: Discussionmentioning

confidence: 83%

Interaction and Assembly of Two Novel Proteins in the Spore Wall of the Microsporidian Species Nosema bombycis and Their Roles in Adherence to and Infection of Host Cells

et al. 2015

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“…Several lines of evidence suggest that this arrest is mediated by the interaction between the major surface protein of sporozoites, the circumsporozoite protein (CSP) and the highly sulfated HSPGs of hepatocytes [35][36][37][38][39]. Recombinant CSP binds specifically to hepatic HSPGs and in vivo, the physiologic ligands for hepatic HSPGs, namely lactoferrin and lipoprotein remnants, delay CSP clearance from the circulation and inhibit sporozoite infection of hepatocytes [40].…”

Section: To the Livermentioning

confidence: 99%

A long and winding road: The Plasmodium sporozoite's journey in the mammalian host

Sinnis

Coppi

2007

Parasitology International

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“…Lactoferrin (aa [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] CAVS QPETKCFQRNMRKI/R yoelii CS, apoE, and lactoferrin. Boldface italics indicate amino acid residues of CS protein required for binding to HSPGs (22).…”

Section: Rklrkrllrdaedlqkrla Vmentioning

confidence: 99%

“…Within minutes after intravenous injection into mice, CS accumulates in the space of Disse on the plasma membrane of hepatocyte microvilli (18). Heparinase treatment of liver sections that have been incubated with CS, and other in vitro experiments using hepatocytes and HepG2 cells as targets, demonstrate that CS binds to HSPGs (19,20). The proteoglycan-binding portion of CS (19,21) is region II-plus (22), a stretch of amino acids highly conserved in all species of malaria parasites (23).…”

mentioning

confidence: 99%

“…Heparinase treatment of liver sections that have been incubated with CS, and other in vitro experiments using hepatocytes and HepG2 cells as targets, demonstrate that CS binds to HSPGs (19,20). The proteoglycan-binding portion of CS (19,21) is region II-plus (22), a stretch of amino acids highly conserved in all species of malaria parasites (23). The region II-plus motif is also found in thrombospondin-related adhesive protein/sporozoite surface protein 2 (TRAP/ SSP2), another surface protein of malaria sporozoites (24,25) that binds to cell surface HSPGs (26,27).…”

mentioning

confidence: 99%

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Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes.

Sinnis

Willnow

Briones

et al. 1996

The Journal of Experimental Medicine

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SummaryRemnants oflipoproteins, intestinal chylomicrons, and very low density lipoproteins (VLDL), are rapidly cleared from plasma and enter hepatocytes. It has been suggested that remnant lipoproteins are initially captured in the space of Disse by heparan sulfate proteoglycans (HSPGs), and that their subsequent internalization into hepatocytes is mediated by members of the LDLreceptor gene family. Similarly to lipoprotein remnants, malaria sporozoites are removed from the blood circulation by the liver within minutes after injection by Anopheles mosquitoes. The sporozoite's surface is covered by the circumsporozoite protein (CS), and its region II-plus has been implicated in the binding of the parasites to glycosaminoglycan chains of hepatocyte HSPGs. Lactoferrin, a protein with antibacterial properties found in breast milk and neutrophil granules, is also rapidly cleared from the circulation by hepatocytes, and can inhibit the hepatic uptake of lipoprotein remnants. Here we provide evidence that sporozoites, lactoferrin, and remnant lipoproteins are cleared from the blood by similar mechanisms. CS, lactoferrin, and remnant lipoproteins compete in vitro and in vivo for binding sites on liver cells. The relevance of this binding event for sporozoite infectivity is highlighted by our demonstration that apoliprotein E-enriched [3-VLDL and lactoferrin inhibit sporozoite invasion of HepG2 cells. In addition, malaria sporozoites are less infective in LDL-receptor knockout (LDLR-/-) mice maintained on a high fat diet, as compared with littermates maintained on a normal diet. We conclude that the clearance oflipoprotein remnants and sporozoites from the blood is mediated by the same set of highly sulfated HSPGs on the hepatocyte plasma membrane.

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Malaria circumsporozoite protein binds to heparan sulfate proteoglycans associated with the surface membrane of hepatocytes.

Cited by 316 publications

References 50 publications

Interaction and Assembly of Two Novel Proteins in the Spore Wall of the Microsporidian Species Nosema bombycis and Their Roles in Adherence to and Infection of Host Cells

Interaction and Assembly of Two Novel Proteins in the Spore Wall of the Microsporidian Species Nosema bombycis and Their Roles in Adherence to and Infection of Host Cells

A long and winding road: The Plasmodium sporozoite's journey in the mammalian host

Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes.

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